Moisture Resistant Container Systems for Rapidly Bioavailable Dosage Forms

ABSTRACT

Provided are rapidly bioavailable solid oral dosage forms of acute pain medications, and moisture resistant packaging that enables the formulation of such rapidly bioavailable dosage forms.

FIELD OF THE INVENTION

The present invention concerns rapidly bioavailable solid oral dosageforms and moisture resistant packaging that enables the formulation ofsuch dosage forms. The invention is particularly concerned withpackaging systems for acute pain medications.

BACKGROUND

The bioavailability of pharmaceutical products is a critical concern inrational drug design. The pharmacokinetics of a drug, which measure thetime it takes a drug to become bioavailable and its concentrationprofile in serum over time, can have a significant effect on theeffectiveness of a drug, as well as its safety. Pharmacokinetics are ofparticular concern for drugs that require an immediate onset of action,such as drugs used in the treatment of acute pain.

Various factors can influence the time it takes for a drug to becomebioavailable in therapeutically effective concentrations. For orallyadministered solid dosage forms, some of the most important parametersinclude the disintegration/dissolution time of the drug, the stabilityand solubility of the molecule in the gastrointestinal tract, and firstpass metabolism, to mention just a few. For some drugs such as potassiumdiclofenac the pH of the formulation can also affect itsbioavailability. For example, it is known that diclofenac potassium hasa tendency to precipitate in an acidic environment, thereby making itless bioavailable. This problem is highlighted in bioavailabilitystudies of Cataflam, a commercially marketed form of diclofenacpotassium, which exhibits two concentration peaks in the bloodstreamwhen orally ingested.

When rapid bioavailability is desired, preferred modes of administrationinclude parenteral, inhalation, mucosal and buccal administration.Tablets and capsules are generally available only in immediate release,extended release, and delayed release formats, and are not typicallyemployed when rapid bioavailability is desired because of the time ittakes for the dosage form to dissolve, and the resulting delay ingastrointestinal absorption. A novel delivery system for orallydelivering diclofenac in a rapidly bioavailable tablet has been proposedin PCT/EP97/02709 (published as WO 97/44023), but solid oral dosageforms based on this type of platform are clearly the exception and notthe rule.

OBJECTS OF THE INVENTION

It is an object of the present invention to increase the rate ofbioavailability of solid oral dosage forms, such as tablets andcapsules.

Another object of the present invention is to increase thebioavailability of acute pain medications.

It is another object to provide packaging for rapidly bioavailable solidoral dosage forms that preserves and enhances their bioavailability,stability and physical handling properties.

SUMMARY OF THE INVENTION

it has unexpectedly been discovered that diclofofenac potassium tablets,particularly those formulated for rapid disintegration and dissolution,can be made to disintegrate and dissolve faster by limiting theirmoisture uptake during storage, and allowing them to become harder overtime. Whereas one would normally expect a tablet to disintegrate fasteras it softens, the inventors have discovered that diclofenac potassiumtablets disintegrate slower when the tablet softens, and that the tabletwill not become softer if it is protected from moisture. In other words,the inventors have discovered that one can make diclofenac potassiumtablets disintegrate faster, and hence be more rapidly bioavailable,simply by preventing them from absorbing moisture during storage. Theseresults are counterintuitive and support the patentability of thepresent invention.

Therefore, in one embodiment the invention provides a method ofpackaging a rapidly bioavailable diclofenac potassium tablet comprising:(a) formulating a potassium diclofenac tablet for rapid bioavailability;and (b) packaging said tablet in a moisture resistant bottle thatprevents said tablet from absorbing more than 2.0 wt. % moisture inthree months when stored at 40° C. and 75% relative humidity. In anotherembodiment, the invention provides a method for treating a patientsuffering from acute pain by administering the tablets packagedaccording to the present invention. Tablets are formulated for rapidbioavailability in the sense that they are specially formulated toquickly disintegrate or dissolve rapidly when ingested in the stomach,for example in less than ten or even five minutes.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical comparison of the dissolution profile of theformulation of Example 3A with a commercial diclofenac formulation.

FIG. 2 is a graphical comparison of the dissolution profile of theformulation of Example 3B with a commercial diclofenac formulation.

FIG. 3 is a graphical depiction of the mean plasma concentration timeprofile in subjects after oral administration of T₁ formulation.

FIG. 4 is a graphical depiction of the mean plasma concentration timeprofile in subjects after oral administration of T₂ formulation.

FIG. 5 is a graphical depiction of the mean plasma concentration timeprofile in subjects after oral administration of a commercialformulation.

FIG. 6 is a graphical overlay of the mean plasma concentration timeprofiles profile in subjects after oral administration of T₁, T₂ and acommercial formulation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions

As used in the specification and claims, the singular forms a, an andthe include plural references unless the context clearly dictatesotherwise. For example, the term a pharmaceutical excipient may refer toone or more pharmaceutical excipients for use in the presently disclosedformulations and methods.

USP means the United States Pharmacopeia and National Formulary (USP23-NF 23). Rockville, Md.: United States Pharmacopeia Convention; 2004,unless stated to the contrary. USP 28 <701> refers to physical test 701,disintegration, contained on pages 2411-2412 of the USP. USP 28 <711>refers to physical test 711, dissolution, contained on pages 2412-2414of the USP.

A dosage form, as used herein, refers to a formulation that is ready foradministration to a subject. As used herein, it specifically refers tosolid dosage forms, including, but not limited to, tablets, capsules andpowders. Tablets are most preferably employed, though it will beunderstood that other solid oral dosage forms can also benefit from theteachings of the present invention. An “intact” dosage form refers to adosage form which is ingested in the form it is provided. Intact dosageforms are therefore to be distinguished from orally disintegratingtablets which disintegrate in the mouth before being ingested, oreffervescent tablets which are dissolved in water before being ingested.In preferred embodiments of this invention, the dosage form is a tablet,and the tablets are ingested in an intact form.

C_(max) refers to the maximum plasma concentration of a drug followingoral administration of the solid oral dosage form to patients.Normalized C_(max) refers to the value obtained by dividing C_(max) intothe dosage strength of the solid oral dosage form.

AUC refers to the area under the curve that tracks the plasmaconcentration (ng/ml) of a drug over a given time following the oraladministration of the solid oral dosage form to patients. AUC can bemeasured from 0 to 12 hours or from 0 to 24 hrs following theadministration and in these cases are referred to as AUC ((0-12)) or AUC((0-24)), respectively.

Normalized AUC is obtained by dividing the AUC into the dosage strengthof the solid oral dosage form of the drug. For example, if the AUC((0-12)) is 160 hr·ng/ml following the oral administration of a solidoral dosage form containing 200 mg of active ingredient, the normalizedAUC ((0-12)) is 0.8 hr·ng/ml/mg.

An excipient is considered “freely soluble” in the context of thisapplication if the excipient meets the requirements for either “freelysoluble” or “very soluble” excipients set forth in the United StatesPharmacopeia. Therefore, an excipient that is “freely soluble” in wateris an excipient for which 10 or fewer parts of water are required todissolve one part of the excipient material at 20° C.

Diclofenac is chemically described as[(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid, and is represented bythe following chemical structure:

When used herein, the term diclofenac means the acetic acid form ofdiclofenac, and any of its pharmaceutically acceptable sails. Therefore,when a weight ratio is given, it will be understood that the ratiorefers to the relative weight of diclofenac acid in the ratio, and therelative weight of diclofenac potassium (or other salt) in the ratio.

Acute pain conditions include pain that is temporary or passing, incontrast to chronic pain that is recurring or constant. Acute painconditions thus include pain deriving from soft tissue disorders such assprains and strains, soft tissue lascerations, migraine attacks, andother painful conditions such as renal colic, acute gout, dysmenorrhoea,and following invasive surgical procedures. While the invention isparticularly useful in the treatment of acute pain, it will also beunderstood that the compositions of the present invention are alsouseful in chronic pain conditions. Examples of chronic pain conditionsinclude rheumatoid arthritis, osteoarthritis, and ankylosingspondylitis; and periarticular disorders such as bursitis andtendonitis.

Reducing Moisture Uptake to Improved Bioavailability

As discussed above, the invention relates to moisture resistantpackaging, and the use of moisture resistant packaging to decrease thedisintegration/dissolution time of diclofenac potassium dosage forms. Inone embodiment the invention provides a method of packaging a rapidlybioavailable diclofenac potassium tablet comprising: (a) formulating asolid oral potassium diclofenac dosage form (preferably a tablet) forrapid bioavailability; and (b) packaging said dosage form in a moistureresistant bottle that prevents said dosage form from absorbing more than4.0 3.0, 2.0 or even 1.0 wt. % moisture in three months when stored at40° C. and 75% relative humidity. In another embodiment the inventionrelates to methods of using rapidly bioavailable diclofenac potassiumdosage forms that are packaged in moisture resistant bottles, andprovides a method of treating acute pain comprising: (a) providing arapidly bioavailable solid oral potassium diclofenac dosage form(preferably a tablet) in a moisture resistant bottle that prevents saiddosage form from absorbing more than 2.0 wt. % moisture in three monthswhen stored at 40° C. and 75% relative humidity; and (h) administeringsaid diclofenac potassium dosage form to a patient suffering from acutepain.

Various methods can be used to ensure that the tablets do not absorbmore moisture than is called for by the present invention. A hermeticseal on the bottle is perhaps most important, which could constitutenothing more than a foil or other laminar seal at the opening to thebottle. A dessicant pouch, such as a silica gel pouch, may also be usedfor absorbing any moisture that does enter the bottle.

The dosage forms are rapidly bioavailable in the sense that they arespecially formulated to disintegrate/dissolve quickly when ingested intothe stomach. Numerous means are available for promoting thedisintegration or dissolution of diclofenac tablets or capsules,including, for example, the shell used for the capsule, formulationexcipients such as disintegrants, pH buffers, effervescing agents,freely soluble excipients, hygroscopic excipients, surfactants thatpromote the disintegration and dissolution of the dosage form and theactive molecule, and counterions of the drug molecule. The dosage formsof the present invention are typically characterized by an inverserelationship between disintegration rate and moisture uptake. Thehardness of the tablets is typically greater than about 4.1 kp, and moretypically greater than about 6.0 or 8.0 kp.

Disintegration times for the dosage foams of the present invention, whentested according to USP 28 <701>, are preferably less than about 20minutes, 15 minutes, 10 minutes, 5 minutes, or even 4 minutes, andgreater than about 1, 2 or 3 minutes, most preferably from about 3 toabout 5 minutes. Dissolution times for the dosage forms of the presentinvention, when tested according to USP 28 <711>, based on the time ittakes to dissolve 90 or 95 wt. % of the drug substance, are preferablyless than about 20 minutes, 15 minutes, 10 minutes, 5 minutes, or even 3minutes, and greater than about 1 or 2 minutes. In a preferredembodiment, the dissolution profile for the dosage forms of the presentinvention is in accordance with the following specification: not lessthan 85, 90 or 95% dissolved after 15 minutes in simulated intestinalfluid (e.g. water) at pH=6.8

Mean t_(max) attained by the dosage forms of the present invention ispreferably less than about 40 minutes, 35 minutes, 30 minutes, 25minutes or 20 minutes, and greater than about 5 minutes, 10 minutes or15 minutes. Mean t_(max) is preferably from about from about 5 to about30 minutes, from about 10 to about 30 minutes, or from about 13 to about27 minutes. The corresponding coefficient of variation for mostdiclofenac tablets is normally in the range of 70-90%, which means thatthe T_(max) is strongly variable and dependent on the physicalcharacteristics of the patient (Physicians' Desk Reference, 52 edition,1998, pag. 1831)). In contrast, the inter-subject coefficient ofvariability for said t_(max) for dosage forms of the present inventionis preferably less than about 80, 75, 60, 50, 49, 46, 40, 35, 30% or25%.

Mean C_(max) attained by the formulations of the present invention, fora 50 mg. formulation, is preferably greater than about 1400 ng/ml (0.028liter⁻¹), 1500 ng/ml (0.03 liter⁻¹), 1600 ng/ml (0.032 liter⁻¹) or 1700ng/ml (0.034 liter⁻¹), and less than about 2500 ng/ml (0.05 liter⁻¹) or2300 ng/ml (0.046 liter⁻¹). A preferred range is 1500-2500, 1700-2500,or 1700-2300 ng/ml for a 50 mg. formulation. The inter-subjectcoefficient of variability for said C_(max) preferably is less thanabout 70, 60, 50, 45 or 40%. in contrast to other commercially marketeddiclofenac formulations, the formulations of the present inventionpreferably display only one meaningful peak blood concentration afteringestion. Compare FIGS. 3 and 4.

Preferred C_(max) and t_(max) ranges for various dosage forms of theinvention are set forth below in Table A:

TABLE A Mean C_(max) (ng/ml) Mean t_(max) (min) 50 mg. 1500-2100;1750-2000; 5-35; 10-30; 12-25; diclofenac tablet 1600-1900 15-20 orcapsule 25 mg. 700-1150; 750-950; 800-900; 5-35; 10-30; 15-30;diclofenac tablet 850-1050; 900-1000 15-25 or capsule 12.5 mg. 350-650;400-600; 450-550 5-35; 10-30; 15-25 diclofenac tablet or capsule

In one embodiment the rapid bioavailability is achieved by incorporatingin the dosage form means for generating a gaseous and alkalineenvironment when orally ingested into the stomach. Suitable means forgenerating a gaseous and alkaline environment that is not harmful to thegastrointestinal mucosa include, but are not limited to, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, calcium carbonate, magnesium carbonate, sodium glycinecarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, andmixtures thereof. Suitable gas generating means are not limited to thosewhich are based upon a reaction which forms carbon dioxide. Reactantswhich evolve oxygen or other gases and which are safe for humanconsumption are also considered within the scope of the presentinvention.

The dosage form also preferably includes a hygroscopic excipient whichmay double as the means for generating an alkaline and gaseousenvironment. Products that at relative humidity of 80% (RH=80%) and 25°C. demonstrate low water absorption ability (lower than 1% during 24hrs) have a hygroscopic point below 80% (j<80% RH) and are notconsidered hygroscopic within the meaning of this invention. Ahygroscopic excipient could thus have the ability to absorb greater thanabout 1 wt. %, 3 wt. %, 5 wt. % or 7 wt. % moisture within a twenty fourhour period in a humidity chamber maintained at 80% RH and 25° C.Alternatively, a hygroscopic excipient could be defined as an excipientthat is able to absorb greater than about 0.75 wt %, 1 wt. %, 2 wt. %, 3wt. % or 4 wt. % moisture within a twenty four hour period in a humiditychamber maintained at 60% RH and 25° C. Various hygroscopic excipientscould be used in practicing the present invention, including variouswater-soluble hygroscopic polyhydroxy compounds or esters thereof suchas glycerol and its mono- and diesters derived from low molecular weightcarboxylic; acids, e.g., monoacetin and diacetin (respectively, glycerylmonoacetate and glyceryl diacetate), ethylene glycol, diethylene glycol,triethylene glycol, 1,3-propanediol, trimethylolethane,trimethylolpropane, pentaerythritol, sorbitol, and the like. Otherexamples of hygroscopic water-swellable materials includepharmaceutically acceptable disintegrants such as crosslinkedpolyvinylpyrrolidone, starch NF, and hygroscopic. In a preferredembodiment the hygroscopic excipient is potassium bicarbonate or sodiumbicarbonate.

The means for generating a gaseous and alkaline environment and/orhygroscopic excipients are typically employed in a weight ratio relativeto the diclofenac of greater than about 1:5, 2:5, 2:1, 3:1 or 5:1. Ifdesired, an upper limit on the buffer:diclofenac ratio can be placed atabout 20:1, 10:1, 5:1, 1:1, 4:5 or 3:5. Ranges can be selected from anytwo of the foregoing values that are mathematically possible. In apreferred embodiment, the buffer:diclofenac weight ratio ranges fromabout 1:5 to about 4:5. As a total percentage of the dosage form, themeans for generating a gaseous and alkaline environment preferably makesup greater than about 5, 7 or 9 wt. % of the dosage form formulation,and less than about 25, 20 or 15 wt. % of the formulation. The meanspreferably yields a pH greater than about 7.0, 7.5, 7.8 or 8.0, and lessthan about 9.2, 9.0, 8.8 or 8.5 when the dosage form is mixed with 50 mlof water at 25 degrees Celsius. Alternatively, the means preferablyyields a pH greater than about 6.8, 7.0, 7.2, or 7.5, and less thanabout 8.8, 8.5, 8.3 or 8.0 when the dosage form is mixed with 200 ml ofwater at 25 degrees Celsius.

Alternatively, the dosage form itself can be characterized by itshygroscopicity. In the present invention, dosage forms that at relativehumidity of 80% (RH=80%) demonstrate low water absorption ability (lowerthan 1% during 24 hrs) have a hygroscopic point below 80% (j<80% RH) andare not hygroscopic at normal conditions. A hygroscopic dosage formcould thus have the ability to absorb greater than about 1 wt. %, 1.25wt. %, 1.5 wt. % or 2 wt. % moisture within a twenty four hour period ina humidity chamber maintained at 80% RH and 25° C. Alternatively, ahygroscopic dosage form could be defined as a dosage form that is ableto absorb greater than about 0.50 wt. %, 0.75 wt. %, 1 wt. %, 1.25 wt.%, or 1.5 wt. % moisture within a twenty four hour period in a humiditychamber maintained at 60% RH and 25° C.

Tests performed on 50 mg, diclofenac potassium tablets of the presentinvention maintained at 25° C. and 60% RH over twenty four hours showedan increase in KF (% water) from 1.995% (at time zero) to 3.456% (after24 hours). Tests performed on 50 mg, diclofenac potassium capsules ofthe present invention maintained at 25° C. and 60% RH over twenty fourhours showed an increase in KF (% water) from 1.905% (at time zero) to2.93% (after 24 hrs.). The final dosage form will not typically containgreater than about 5 wt. % water, initially or after 1, 2 or 3 years ofstorage.

The dosage form can also be formulated to be rapidly bioavailable byincorporating at least 20 wt. %, 30 wt %, 40 wt. %, 50 wt. %, or 60 wt.% of excipients that are freely soluble in water. An excipient isconsidered freely soluble in the context of this application if 1 partof excipient is soluble in 1-10 parts of water at 20° C. Examples offreely soluble excipients include mannitol, dextrates (i.e. a purifiedmixture of saccharides resulting from the controlled enzymatichydrolysis of starch), dextrin, dextrose, fructose, lactilol, lactoseanhydrous, sorbitol, sucrose, and compressible sugar. Of these, mannitoland lactilol are particularly preferred due to their beneficialnon-hygroscopic properties, which improves their processability andhandling during the manufacturing process. In a preferred embodiment thedosage form will comprise from about 30 to about 80 wt. % of thecombined hygroscopic diluent and freely soluble diluent, from about 35to about 75 wt. % of the combined hygroscopic diluent and freely solublediluent, or from about from about 40 to about 70 wt. % of the combinedhygroscopic diluent and freely soluble diluent. In addition, thehygroscopic diluent and freely soluble excipient will preferably bepresent in a weight ratio of from about 1:20 to about 5:1, from about1:10 to about 3:1, from about 1:8 to about 1:1, from about 1:8 to about1:2, or from about 1:4 to about 1:1.

Yet another way to render the dosage forms rapidly bioavailable is toincorporate a surfactant that aids in the solubility of the dosage form,such as sodium lauryl sulfate. Preferred surfactants will have an HLBvalue of at least 10 or 12, and preferably at least about 14 or 15. Anupper bound can also be placed on the HLB of the surfactant, preferablyof 60, 50 or 40. In certain preferred embodiments, the HLB value of thesurfactant is from about 15 to 60, and in further embodiments the HLB ismost preferably from about 20 to about 50. Suitablepharmaceutically-acceptable anionic surfactants include, for example,those containing carboxylate, sulfonate, and sulfate ions. The mostcommon cations associated with these surfactants are sodium, potassium,ammonium and triethanolamine. The chain length of the fatty acidstypically range from 12 to 18. Although a large number of alkyl sulfatesare available as surfactants, one particularly preferred surfactant issodium lauryl sulfate, which has an HLB value of about 40. Othersuitable wetting agents include glyceryl monooleate, sorbitan ester,docusate sodium, and cetrimide.

A preferred class of acute pain medications for use in the presentinvention are non-steroidal anti-inflammatory drugs including, amongothers, fenamic acid derivatives, indene derivatives, and ibufenacderivatives. Csáky and Barnes in “Cutting's Handbook of Pharmacology,”Appleton-Century-Crofts, Norwalk, Conn. (1984). Fenamic acid derivativesare broadly classified as o˜anilino derivatives of benzoic,phenylacetic, and nicotinic acids and are defined by Csáky and Barnes asincluding flufenemic acid, mefenamic acid, meclofenamic acid,clonixeril, clonixin, flunixin, and diclofenac, including thepharmaceutically acceptable salts thereof. Indene derivatives generallyare acetic acid, propionic acid, and benzoic acid derivatives containinga pyrrole (or a pyrazole, pyrroline or pyrrolidine) ring and are definedby Csáky and Barnes as including indomethacin, carprofen, etodolac,fendosal, indoprofen, prodolic acid, sermetacin, zidometacin, andzomeprirac, including the pharmaceutically acceptable salts thereof.Compounds not so classified by Csáky and Barnes but related in beingacetic acid, propionic acid, or benzoic acid, derivatives and here soclassified include tolmetin, sulinac, cicloprofen, and cinchophen,including the pharmaceutically acceptable salts thereof. Ibufenacderivatives are acetic and propionic acid derivatives bearing asubstituted aromatic hydrocarbon ring, such as phenyl or naphthyl, andare defined by Csáky and Barnes as including ifiunisal, fenoprofen,ibuprofen, naproxen, alclofenac, amfenac, cliprofen, fenclofenac,fenclorac, suprofen, ketoprofen, naproxol, fenbufen, and ibufenac;including the pharmaceutically acceptable salts thereof.

Diclofenac acid and its pharmaceutically acceptable salts are aparticularly preferred acute pain medication, especially diclofenacpotassium. Other pharmaceutically acceptable salts include those ofsodium and other alkali and alkaline earth metals, or salts of organicnature, such as the salts of basic amino acids, such as lysine, arginineand ornithine. In a preferred embodiment, 10-60 mg. or 50 mg. ofdiclofenac potassium is used in the final dosage form, although otheramounts could be used including 12.5, 25, 37.5, 75 or 100 mg. Thediclofenac preferably has a loss on drying of not less than 0.5%, and anaverage particle size of greater than 100 microns, and less than 400microns.

EXAMPLES Example 1 Tablet Core Formulations

Uncoated diclofenac tablets containing 50 mg, of diclofenac potassiumwere prepared based on the formulations given in Table I below.Formulations were prepared using alcoholic granulation (Tablet C) anddirect compression (Tablet B).

TABLE 1 Tablet C Tablet B (alcoholic (direct Names of ingredientsgranulation) compression) Function Standard Active ingredientsDiclofenac potassium 50 mg.* 50 mg Active ingredient Eur. Ph. Tabletcores excipients Potassium hydrogen carbonate 22 22 Buffering agent Eur.Ph. Mannitol 50 119.9 Diluent and Eur. Ph. disintegrating agent Maizestarch 25 / Binder diluent Eur. Ph. Methocel A4C 0.2 / Thichener Eur.Ph. Crospovidone 1.0 6.0 Binder Eur. Ph. Sodium lauryl sulphate 0.1 0.1Solubilizing agent Eur. Ph. Magnesium stearate 4.5 2.0 Lubricant agentEur. Ph. Ultramyl 2.5 / Lubricant agent Eur. Ph. Aerosil 1.0 / Lubricantagent Eur. Ph. Total weight 156.3 200.0 mg *Units are in milligramsunless otherwise specified.

Example 2 Stability Testing

Stability tests were conducted in various blister packaging materials onthe tablet cores (Tablet B and Tablet C), and on Tablet B tablets coatedwith an aqueous polymer coating, suspension (Tablet BA) and an alcoholicpolymer coating solution (Tablet BB). Stability testing was restrictedto three different blister types. The properties of the forming andlidding films used in the three blister materials tested are as follows:

-   -   PVDC—coated PVC and hard aluminum (25 μm, coated on the        underside with a vinyl lacquer) are the materials of the forming        film and the lidding part of the tested blister 1, respectively.        The thickness of the PVDC coat is 40 μm while that of the PVC        film is 250 μm.    -   PVDC—coated PVC and hard aluminum (25 μm, coated on the        underside with a vinyl lacquer) are the materials of the forming        film and the lidding part of the tested blister 2, respectively.        The thickness of the PVDC coat is 80 μm while that of the PVC        film is 250 μm.    -   OPA/Al/PVC and hard aluminum (25 μm, coated on the underside        with a vinyl lacquer) are the materials of the forming film and        the lidding part of the tested blister 3, respectively. Nylon        (Oriented Polyamide)-Aluminum-PVC (OPA/Al/PVC) is a laminate,        which consists of 25 μm OPA/45 μm aluminum/60 μm PVC.

An appropriate quantity of tablet cores (Tablets B and C) and coatedtablets (Tablets BA and BB), in original packaging (blisters 1-3) wasstored in Weiss-Enet climatic chambers for six months under thefollowing conditions of temperature and relative humidity:

Temperature (° C.) Relative humidity (±1%) 25 60 30 60 40 75

Samples were withdrawn at suitable intervals and subjected to testingfor Diameter, Thickness, Hardness, Weight, Disintegration time in water(37° C.), Water content, Dissolution buffered pH 7.5 medium, and Assay.The measurements were performed on six tablet cores or coated tabletstaken at random in all instances, and the average values were recorded.The results are given in Tables 2-7 below,

TABLE 2 Influence of packaging material (blisters 1, 2 and 3) on thestability of Tablets B and C stored at 25° C. (RH = 60%)^(a) TabletTablet B Tablet B Tablet B Tablet Tablet C Tablet C Tablet C B^(b)Blister 1^(c) Blister 2 Blister 3 C^(d) Blister 1^(c,e) Blister 2^(e)Blister 3^(e) Time 3 6 3 6 3 6 Time 3 6 3 6 3 6 Tests zero months monthsmonths months months months zero months months months months monthsmonths Diameter^(f) 7.0 7.0 / 7.1 7.1 7.0 7.1 7.0 7.0 / 7.0 / 7.0 / (mm)Thickness^(f) 4.4 4.4 / 4.4 4.5 4.4 4.4 3.5 3.6 / 3.5 / 3.5 / (mm)Hardness^(f) 71 65 / 65 63 71 74 31 24 / 25 / 32 / (N) Weight 198 201 /200 199 199 198 154 157 / 155 / 155 / (mg) Water 2.4 3.2 / 2.8 2.7 2.62.5 3.5 3.5 / 5.0 / 4.2 / content^(g) (%) Disintegration 2:50 6:12 /3:43 3:56 2:33 2:33 3:05 2:28 / 2:23 / 2:12 / time^(h) (min.:sec.)Dissolution^(i) 93 96 / 98 96 95 99 95 96 / 98 / 97 / after 20 min. (%)Assay^(j) 96.6 95.6 / 96.0 96.2 99.8 99.0 97.0 96.4 / 97.8 / 99.2 / (%)^(a)All values are average values determined on six units taken atrandom. ^(b)Matrix tablets produced by direct compression of the mixtureF11 with a rotary tablet machine. ^(c)Stability in blister 1 wasinterrupted after 3 months. ^(d)Matrix tablets produced from the mixtureF3 (alcoholic granulation) with a rotary tablet machine. ^(e)Stabilityof batch no. 990310C was interrupted after 3 months. ^(f)Erweka TBH 30HD apparatus. ^(g)Determined according to Eur. Ph. (Karl Fischersemi-micro water determination). ^(h)Determined in water (37° C.)according to Eur. Ph.. ^(i)Determined in buffered pH 7.5 mediumaccording to Eur. Ph.. ^(j)Determined by high performance liquidchromatography (HPLC).

TABLE 3 Influence of packaging material (blisters 1, 2 and 3) on thestability of Tablets B and C stored at 30° C. (RH = 60%)^(a) TabletTablet B Tablet B Tablet B Tablet Tablet C Tablet C Tablet C B^(b)Blister 1^(c) Blister 2 Blister 3 C^(d) Blister 1^(c,e) Blister 2^(e)Blister 3^(e) Time 3 6 3 6 3 6 Time 3 6 3 6 3 6 Tests zero months monthsmonths months months months zero months months months months monthsmonths Diameter^(f) 7.0 7.1 / 7.1 7.1 7.1 7.1 7.0 7.1 / 7.0 / 7.0 / (mm)Thickness^(f) 4.4 4.5 / 4.5 4.5 4.4 4.5 3.5 3.6 / 3.6 / 3.4 / (mm)Hardness^(f) 71 66 / 60 64 72 71 31 24 / 27 / 31 / (N) Weight 198 202 /200 202 199 199 154 158 / 157 / 154 / (mg) Water 2.4 6.4 / 3.6 3.1 2.22.5 3.5 6.4 / 5.7 / 4.0 / content^(g) (%) Disintegration 2:50 5:32 /5:09 5:49 2:40 2:30 3:05 2:17 / 2:09 / 2:35 / time^(h) (min.:sec.)Dissolution^(i) 93 95 / 94 95 93 96 95 97 / 96 / 98 / after 20 min. (%)Assay^(j) 96.6 94.2 / 95.4 96.0 96.0 96.4 97.0 97.2 / 97.2 / 100.0 / (%)

TABLE 4 Influence of packaging material (blisters 1, 2 and 3) on thestability of Tablets B and C stored at 40° C. (RH = 75%)^(a) TabletTablet B Tablet B Tablet B Tablet Tablet C Tablet C Tablet C B^(b)Blister 1^(c) Blister 2 Blister 3 C^(d) Blister 1^(c,e) Blister 2^(e)Blister 3^(e) Time 3 6 3 6 3 6 Time 3 6 3 6 3 6 Tests zero Months monthsmonths months months months zero months months months months monthsmonths Diameter^(f) 7.0 7.2 / 7.1 7.1 7.0 7.1 7.0 7.1 / 7.0 / 7.0 / (mm)Thickness^(f) 4.4 4.5 / 4.5 4.6 4.6 4.4 3.5 3.7 / 3.6 / 3.5 / (mm)Hardness^(f) 71 64 / 67 62 71 70 31 23 / 27 / 30 / (N) Weight 198 205 /201 205 198 200 154 161 / 158 / 154 / (mg) Water 2.4 5.3 / 3.6 5.2 2.12.2 3.5 7.3 / 6.2 / 4.0 / content^(g) (%) Disintegration 2:50 7:20 /6:16 6:12 3:17 3:31 3:05 2:27 / 2:28 / 2:23 / time^(h) (min.:sec.)Dissolution^(i) 93 92 / 95 96 94 95 95 92 / 95 / 94 / after 20 min. (%)Assay^(j) 96.6 92.6 / 92.6 92.2 96.0 96.3 97.0 97.2 / 96.4 / 99.4 / (%)

TABLE 5 Influence of packaging material (blisters 1, 2 and 3) on thestability of film-coated Tablets BA and BB stored at 25° C. (RH =60%)^(a) Tablet Tablet BA Tablet BA Tablet BA Tablet Tablet BB Tablet BBTablet BB BA^(b) Blister 1^(c) Blister 2 Blister 3 BB^(d) Blister 1^(c)Blister 2 Blister 3 Time 3 6 3 6 3 6 Time 3 6 3 6 3 6 Tests zero monthsmonths months months months months zero months months months monthsmonths months Diameter^(f) 7.1 7.1 / 7.1 7.1 7.1 7.2 7.1 7.1 / 7.1 7.27.1 7.2 (mm) Thickness^(f) 4.6 4.6 / 4.5 4.6 4.5 4.5 4.5 4.6 / 4.5 4.74.5 4.5 (mm) Hardness^(f) 128 116 / 108 103 127 130 114 108 / 112 95 114116 (N) Weight 204 206 / 204 205 204 204 203 207 / 204 211 203 204 (mg)Water 2.5 4.4 / 2.9 3.0 2.1 3.2 2.3 3.5 / 2.8 3.1 2.3 3.0 content^(g)(%) Disintegration 3:23 6:15 / 4:28 4:42 3:24 4:28 3:26 7:00 / 4:09 9:023:13 4:12 time^(h) (min.:sec.) Dissolution^(i) 93 95 / 96 98 94 95 96 93/ 94 94 97 96 after 20 min. (%) Assay^(j) 95.8 95.0 / 96.0 96.3 98.498.7 95.6 93.4 / 94.4 94.0 96.4 96.8 (%)

TABLE 6 Influence of packaging material (blisters 1, 2 and 3) on thestability of film-coated Tablets BA and BB stored at 30° C. (RH =60%)^(a) Tablet Tablet BA Tablet BA Tablet BA Tablet Tablet BB Tablet BBTablet BB BA^(b) Blister 1^(c) Blister 2 Blister 3 BB^(d) Blister 1^(c)Blister 2 Blister 3 Time 3 6 3 6 3 6 Time 3 6 3 6 3 6 Tests zero monthsmonths months months months months zero months months months monthsmonths months Diameter^(f) 7.1 7.1 / 7.1 7.1 7.1 7.1 7.1 7.1 / 7.1 7.17.1 7.1 (mm) Thickness^(f) 4.6 4.6 / 4.5 4.6 4.5 4.5 4.5 4.6 / 4.5 4.64.3 4.6 (mm) Hardness^(f) 128 103 / 110 110 130 128 114 99 / 104 100 112114 (N) Weight 204 206 / 205 206 204 203 203 207 / 206 206 203 203 (mg)Water 2.5 5.5 / 3.1 3.6 2.2 3.0 2.3 4.1 / 3.2 3.8 3.3 2.6 content^(g)(%) Disintegration 3:23 5:59 / 4:33 6.11 3:39 3:51 3:26 5:54 / 6:29 5:223:40 4:00 time^(h) (min.:sec.) Dissolution^(i) 93 95 / 96 95 94 97 96 94/ 96 93 93 96 after 20 min. (%) Assay^(j) 95.8 94.8 / 94.4 96.8 96.898.2 95.6 94.6 / 94.0 98.5 97.8 97.0 (%)

TABLE 7 Influence of packaging material (blisters 1, 2 and 3) on thestability of film-coated Tablets BA and BB stored at 40° C. (RH =75%)^(a) Tablet Tablet BA Tablet BA Tablet BA Tablet Tablet BB Tablet BBTablet BB BA^(b) Blister 1^(c) Blister 2 Blister 3 BB^(d) Blister 1^(c)Blister 2 Blister 3 Time 3 6 3 6 3 6 Time 3 6 3 6 3 6 Tests zero monthsmonths months months months months zero months months months monthsmonths months Diameter^(f) 7.1 7.1 / 7.2 7.2 7.1 7.1 7.1 7.2 / 7.1 7.17.1 7.1 (mm) Thickness^(f) 4.6 4.6 / 4.6 4.7 4.5 4.6 4.5 4.6 / 4.6 4.64.5 4.6 (mm) Hardness^(f) 128 102 / 110 104 130 125 114 93 / 102 99 115111 (N) Weight 204 209 / 207 210 204 204 203 210 / 208 204 204 203 (mg)Water 2.5 5.3 / 4.2 5.0 2.2 2.7 2.3 5.2 / 4.2 5.6 3.1 3.6 content^(g)(%) Disintegration 3:23 7:18 / 6:51 6:48 3:50 3:30 3:26 9:16 / 6:45 4:184:15 3:16 time^(h) (min.:sec.) Dissolution^(i) 93 93 / 94 96 95 96 96 94/ 95 96 97 96 after 20 min. (%) Assay^(j) 95.8 95.0 / 95.4 98.1 98.296.3 95.6 94.0 / 95.6 96.7 98.0 95.2 (%)

Example 3 Diclofenac K Tablet Dissolution Profile Comparison

Using the dissolution test procedure described in the EuropeanPharmacopeia, the dissolution profiles for two tablets (Ex. 3a and 3b)having the composition set forth in Table 8 were generated. The onlydifference between the two tablets was the source of the diclofenacpotassium. Dissolution profiles of 50 mg. diclofenac potassium tabletsmarketed as Voltaren Rapid and Voltfast were also generated, and graphsof the contrasting dissolution profiles were superimposed, to produceFIGS. 1 and 2 hereto.

TABLE 8 Composition of Test Formulations Reference to Names ofIngredients Unit (mg.) Function Standards Drug Substance DiclofenacPotassium 50.0 Anti-inflammatory agent Eur. Ph. Matrix Tablet ExcipientsPotassium Bicarbonate 22.0 Buffering Agent Eur. Ph. Mannitol 116.4Diluent and Disintegrant Eur. Ph. Agent Sodium Lauryl Sulfate 0.1Solubilizing Agent Eur. Ph. Macrogols (as Macrogol 6000) 1.5 LubricantAgent Eur. Ph. Crospovidone 6.0 Binder Eur. Ph. Magnesium Stearate 4.0Lubricant Agent Eur. Ph. Film-Coating Excipients Clear Opadry 4.0Coating Agent In House Specifications Total Weight 204.0

Example 4 Diclofenac K Tablet Pharmacokinetic Profile Comparison

A further comparative test was carried out on immediate releaseformulations T1 and T2, as reported below in Table 9, A comparativebioavailability study was carried out on 6 healthy volunteers of bothsexes in order to evaluate the in vivo results of the pharmacokineticprofiles of the present formulations if compared to those of abioequivalent fast release formulation such as Voltaren Rapid® (50 mg ofdiclofenac potassium), by Novartis. The results, which are reported inFIGS. 3-6 are also in this case excellent: the T_(max) is in factprompter with the present formulations (T1=18.6 min, T2=16.8 mM vs R140.8 min) and the C_(max) is higher (T1=1878.3 ng/ml and T2=1744.8 ng/mlvs R1 1307 ng/ml); furthermore, also in this case the T_(max) of bothpresent formulations shows a coefficient of variation lower thanreference formulation (T1=12.9% and T2=25% vs R1=95.6%).

TABLE 9 Formulation of Comparison Tablets Reference, K salt, 50 mg, T1,K salt, 50 mg, tablets T2, K salt, 50 mg, tablets Voltaren ® Rapidtablets Description Diclofenac potassium Diclofenac potassium Diclofenacpotassium 50 mg film-coated tablets 50 mg film-coated tablets 50 mgfilm-coated tablets (by alcoholic granulation) (by direct compression)Active Diclofenac potassium mg 50 Diclofenac potassium mg 50 Diclofenacpotassium mg 50 ingredient Excipients Potassium bicarbonate mg 22Potassium bicarbonate mg 22 Calcium phosphate Mannitol mg 50 Mannitol400 mg 119.9 Saccharose Maize starch mg 25 Sodium laurylsulfate mg 0.1Maize starch Hydroxypropylmethylcellulose mg Polyvinylpyrrolidone mg 6Talc 0.2 Magnesium stearate mg 2 Sodium Sodium laurylsulfate mg 0.1 FilmCoating Opadry Clear carboxymethylcellulose Polyvinylpyrrolidone mg 1(HPMC 2910, Colloidal anhydrous silicium Sodium starch glycollate mg 2.5polyethyleneglycol 400) mg 4 Polyvinylpyrrolidone Magnesium stearate mg4.5 Microcrystalline cellulose Silicium aerosil FK 160 mg 1 Magnesiumstearate Coating Opadry Clear (HPMC Polyethylenglycole 2910 andpolyethyleneglycol 400) Titanidioxide (E171) mg 4 Iron oxide red (E172)Total weight 160.3 mg 204 mg

TABLE 10 Pharmacokinetics of Comparison Tablets. PK results Test 1 (K,Test 2 (K, Reference (K, tablets 50 mg) tablets 50 mg) tablets 50 mg)C_(max) Mean 1873.30 1744.8 1307.0 SD 553.80 572.3 558.4 CV % 29.5 32.842.7 Min 1228.9 1057.4 581.8 Max 2516.5 2468.9 1935.5 AUC Mean 1219 12371168 SD 246 276 282 CV % 20.2 22.3 24.1 Min 874 848 913 Max 1615 16681642 t_(max) Mean 0.31 h (18.6 min) 0.28 h (16.8 min) 0.68 h (40.8 min)SD 0.04 0.07 0.65 CV % 12.9 25.0 95.6 Min 0.25 h (15 min)   0.17 h (10.2min) 0.25 h (15 min)   Max 0.33 h (19.8 min) 0.33 h (19.8 min) 2.00 h(120 min) 

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertain. It willbe apparent to those skilled in the art that various modifications andvariations can be made in the present invention without departing fromthe scope or spirit of the invention. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly, with a true scope and spirit of the invention being indicated bythe following claims.

1-20. (canceled)
 21. A method comprising: a) providing a moistureresistant package that prevents the dosage form described in step (b)from absorbing more than 4 wt. % moisture in three months when stored at40° C. and 75% relative humidity; b) providing a 10-60 mg. diclofenacpotassium solid oral tablet dosage form formulated for rapidbioavailability, in a formulation comprising: i) at least 20 wt. % ofone or more buffers and/or alkalizing agents, based on the weight ofdiclofenac in its acid form; and ii) from about 30 to about 80 wt % of ahygroscopic diluent based on the weight of the tablet and said one ormore freely soluble diluents at a weight ratio of from about 1:20 toabout 5:1, wherein said hygroscopic diluent absorbs greater than about0.5 wt. % water within a twenty four hour period in a humidity chambermaintained at 60% relative humidity (“RH”) and 25° C.; c) providing saiddosage form in said package; and d) administering said dosage form to ahuman in need thereof.
 22. The method of claim 21 wherein said rapidbioavailability has been shown to comprise a time to maximum plasmaconcentrations (t_(max)) of from about 5 to about 30 minutes, and amaximum plasma concentration (C_(max)) of from about 1700 to about 2300ng/ml.
 23. The method of claim 21 wherein said rapid bioavailability hasbeen established to comprise a time to maximum plasma concentrations(t_(max)) of from about 13 to about 27 minutes, and a maximum plasmaconcentration (C_(max)) of from about 1500 to about 2500 ng/ml whereinsaid t_(max) has exhibited an inter-subject variability of less thanabout 49%.
 24. The method of claim 21 wherein said dosage form has beenshown to yield one maximum plasma concentration (C_(max)) peak whenorally ingested.
 25. The method of claim 21 wherein said containercomprises a foil seal at the cap and one or more dessicant pouchesinside said container.
 26. The method of claim 21 wherein said dosageform comprises from about 7 to about 20 wt. % of an excipient thatabsorbs greater than about 1 wt. % water within a twenty four hourperiod in a humidity chamber maintained at 80% RH and 25° C.
 27. Themethod of claim 21 wherein said dosage form absorbs greater than about 1wt. % water within a twenty four hour period in a humidity chambermaintained at 80% RH and 25° C.
 28. The method of claim 21 wherein saiddosage form further comprises at least 20 wt. % of mannitol, lactose,sucrose, or a combination thereof.
 29. The method of claim 21 whereinsaid dosage form further comprises a surfactant.
 30. The method of claim21 wherein said dosage form further comprises a surfactant having ahydrophilic lipophilic balance (“HLB”) greater than
 14. 31. The methodof claim 21 wherein said dosage form further comprises sodium laurylsulfate.
 32. The method of claim 21 wherein said dosage form furthercomprises an excipient base that comprises an inverse relationshipbetween disintegration rate and moisture uptake.
 33. A methodcomprising: a) providing a moisture resistant package that prevents thedosage form described in step (b) from absorbing more than 4 wt. %moisture in three months when stored at 40° C. and 75% relativehumidity; b) providing a 50 mg. diclofenac potassium solid oral tabletdosage form formulated for rapid bioavailability, in a formulationcomprising: i) at least 20 wt. % of one or more buffers and/oralkalizing agents, based on the weight of diclofenac in its acid form;and ii) from about 30 to about 80 wt % of a hygroscopic diluent based onthe weight of the tablet and said one or more freely soluble diluents ata weight ratio of from about 1:20 to about 5:1, wherein said hygroscopicdiluent absorbs greater than about 0.5 wt. % water within a twenty fourhour period in a humidity chamber maintained at 60% relative humidity(“RH”) and 25° C.; c) providing said dosage form in said package; and d)administering said dosage form to a human in need thereof.
 34. Themethod of claim 33 wherein said dosage form has been shown to yield onemaximum plasma concentration (C_(max)) peak when orally ingested. 35.The method of claim 33 wherein said dosage form comprises from about 7to about 20 wt. % of an excipient that absorbs greater than about 1 wt.% water within a twenty four hour period in a humidity chambermaintained at 80% RH and 25° C.
 36. The method of claim 33 wherein saiddosage form absorbs greater than about 1 wt. % water within a twentyfour hour period in a humidity chamber maintained at 80% RH and 25° C.37. The method of claim 33 wherein said hygroscopic excipient comprisesmannitol, lactose, sucrose, or a combination thereof.
 38. The method ofclaim 33 wherein said dosage form further comprises a surfactant. 39.The method of claim 33 wherein said dosage form further comprises asurfactant having a hydrophilic lipophilic balance (“HLB”) greater than14.
 40. The method of claim 33 wherein said dosage form furthercomprises sodium lauryl sulfate.
 41. The method of claim 21 wherein saiddosage form further comprises an excipient base that comprises aninverse relationship between disintegration rate and moisture uptake.42. The method of claim 21 where said one or more buffers and/oralkalizing agents are freely soluble in water.
 43. The method of claim21 wherein said method comprising: a) providing a moisture resistantpackage that prevents the dosage form described in step (b) fromabsorbing more than 4 wt. % moisture in three months when stored at 40°C. and 75% relative humidity; b) providing a 10-60 mg. diclofenacpotassium solid oral tablet dosage form formulated for rapidbioavailability, in a formulation comprising: i) at least 20 wt. % ofone or more buffers, based on the weight of diclofenac in its acid form;and ii) from about 30 to about 80 wt % of a hygroscopic diluent based onthe weight of the tablet and said one or more freely soluble diluents ata weight ratio of from about 1:20 to about 5:1, wherein said hygroscopicdiluent absorbs greater than about 0.5 wt. % water within a twenty fourhour period in a humidity chamber maintained at 60% relative humidity(“RH”) and 25° C.; c) providing said dosage form in said package; and d)administering said dosage form to a human in need thereof.
 44. Themethod of claim 21 wherein said method comprising: a) providing amoisture resistant package that prevents the dosage form described instep (b) from absorbing more than 4 wt. % moisture in three months whenstored at 40° C. and 75% relative humidity; b) providing a 10-60 mg.diclofenac potassium solid oral tablet dosage form formulated for rapidbioavailability, in a formulation comprising: i) at least 20 wt. % ofone or more alkalizing agents, based on the weight of diclofenac in itsacid form; and ii) from about 30 to about 80 wt % of a hygroscopicdiluent based on the weight of the tablet and said one or more freelysoluble diluents at a weight ratio of from about 1:20 to about 5:1,wherein said hygroscopic diluent absorbs greater than about 0.5 wt. %water within a twenty four hour period in a humidity chamber maintainedat 60% relative humidity (“RH”) and 25° C.; c) providing said dosageform in said package; and d) administering said dosage form to a humanin need thereof.
 45. The method of claim 33 where said one or morebuffers and/or alkalizing agents are freely soluble in water.
 46. Themethod of claim 33 wherein said method comprising: a) providing amoisture resistant package that prevents the dosage form described instep (b) from absorbing more than 4 wt. % moisture in three months whenstored at 40° C. and 75% relative humidity; b) providing a 50 mg.diclofenac potassium solid oral tablet dosage form formulated for rapidbioavailability, in a formulation comprising: i) at least 20 wt. % ofone or more buffers, based on the weight of diclofenac in its acid form;and ii) from about 30 to about 80 wt % of a hygroscopic diluent based onthe weight of the tablet and said one or more freely soluble diluents ata weight ratio of from about 1:20 to about 5:1, wherein said hygroscopicdiluent absorbs greater than about 0.5 wt. % water within a twenty fourhour period in a humidity chamber maintained at 60% relative humidity(“RH”) and 25° C.; c) providing said dosage form in said package; and d)administering said dosage form to a human in need thereof.
 47. Themethod of claim 33 wherein said method comprising: a) providing amoisture resistant package that prevents the dosage form described instep (b) from absorbing more than 4 wt. % moisture in three months whenstored at 40° C. and 75% relative humidity; b) providing a 50 mg.diclofenac potassium solid oral tablet dosage form formulated for rapidbioavailability, in a formulation comprising: i) at least 20 wt. % ofone or more alkalizing agents, based on the weight of diclofenac in itsacid form; and ii) from about 30 to about 80 wt % of a hygroscopicdiluent based on the weight of the tablet and said one or more freelysoluble diluents at a weight ratio of from about 1:20 to about 5:1,wherein said hygroscopic diluent absorbs greater than about 0.5 wt. %water within a twenty four hour period in a humidity chamber maintainedat 60% relative humidity (“RH”) and 25° C.; c) providing said dosageform in said package; and d) administering said dosage form to a humanin need thereof.